Nocturnal wheezing is an integral and important feature of asthma. For many patients, nighttime exacerbations of asthma are frequent and often serious. Yet to be determined, however, are the mechanisms that cause nocturnal asthma. The long-term goal of this project is to establish the causes of nighttime airflow obstructions and critical factors involved in this process. To achieve this goal, evidence has been obtained that circadian variations in epinephrine and possibly cortisol, and sleep are important, independent and interactive factors for nighttime airflow obstruction and airway inflammation. Therefore, it is hypothesized that a mechanism of nocturnal asthma is the circadian fall in epinephrine and cortisol which promotes airway inflammation through the release or generation of phlogistic cytokines. Furthermore, it is hypothesized that sleep is also an independent contributor to this process through enhanced release of pro-inflammatory cytokines.
Specific aims of this proposal are designed to determine the separate contributions of circadian patterns (epinephrine and cortisol) and sleep to nocturnal asthma. To accomplish these goals, asthma patients will be identified and studied on four different hospitalized occasions with awake-sleep cycles varied. The four study periods are designed to determine the individual, and potentially interactive, influences of circadian rhythms(as measured by plasma epinephrine and cortisol) and sleep on pulmonary physiology, airway inflammation and airway and blood cell biology. The effect of these variables on pulmonary physiology, will be confirmed by spirometry. In addition, bronchoalveolar lavage (BAL) will be performed on each study occasion. BAL fluid will be used to quantitate airway inflammation by cell counts, lymphocyte markers (e.g. CD4, CD8, CD25), mediators (histamine and tryptase) and protein. Airway cell biology, e.g. generation of superoxide presence of eosinophil granular proteins (representing activation and release), concentrations of cytokines(IL-1, IL-4, IL-5, GM-CSF, TNF-gamma, and INF-gamma), and expression of mRNA for these cytokines, will be measured. Furthermore, to ascertain whether changes in cell function in nocturnal asthma are compartmentalized to the airway, peripheral blood cells will be used for lymphocytes surface markers, lymphocyte release of cytokines and expression of its mRNA, and eosinophil in vitro survival. The independent, and interactive, influences of circadian patterns and sleep to changes in physiology, inflammation and cell biology will then be determined. These observations will provide new information on the mechanisms of nocturnal asthma and insight into regulation of pulmonary inflammation.
| Hla, K Mae; Skatrud, James B; Finn, Laurel et al. (2002) The effect of correction of sleep-disordered breathing on BP in untreated hypertension. Chest 122:1125-32 |
